Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Oct 26;10(11):780.
doi: 10.3390/brainsci10110780.

hATTR Pathology: Nerve Biopsy Results from Italian Referral Centers

Marco Luigetti  1   2 , Marina Romozzi  1   2 , Giulia Bisogni  3 , Davide Cardellini  4 , Tiziana Cavallaro  4 , Andrea Di Paolantonio  2 , Gian Maria Fabrizi  4 , Silvia Fenu  5 , Luca Gentile  6 , Marina Grandis  7   8 , Gianluca Marucci  9 , Sara Massucco  7 , Anna Mazzeo  6 , Davide Pareyson  5 , Angela Romano  2   3 , Massimo Russo  6 , Angelo Schenone  7   8 , Matteo Tagliapietra  4 , Stefano Tozza  10 , Giuseppe Vita  6 , Mario Sabatelli  2   3
Affiliations

hATTR Pathology: Nerve Biopsy Results from Italian Referral Centers

Marco Luigetti et al. Brain Sci. .

Abstract

Pathological evidence of amyloid on nerve biopsy has been the gold standard for diagnosis in hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) for a long time. In this article, we reviewed the pathological findings of a large series of sural nerve biopsies from a cohort of hATTR-PN patients, collected by different Italian referral centers. Patients and Methods: We reviewed clinical and pathological data from hATTR-PN patients, diagnosed and followed in five Italian referral centers for peripheral neuropathies. Diagnosis was formulated after a positive genetic test for transthyretin (TTR) mutations. Sural nerve biopsy was performed according to standard protocols. Results: Sixty-nine sural nerve biopsies from hATTR-PN patients were examined. Congo red positive deposits were found in 73% of cases. Only the Phe64Leu mutation failed to show amyloid deposits in a high percentage of biopsies (54%), as already described. Unusual pathological findings, such as myelin abnormalities or inflammatory infiltrates, were detected in occasional cases. Conclusions: Even if no longer indicated to confirm hATTR-PN clinical suspicion, nerve biopsy remains, in expert hands, a rapid and inexpensive tool to detect amyloid deposition. In Italy, clinicians should be aware that a negative biopsy does not exclude hATTR-PN, particularly for Phe64Leu, one of the most frequent mutations in this country.

Keywords: Congo red; amyloid; axonal loss; hATTR; nerve biopsy; polyneuropathy.

PubMed Disclaimer

Conflict of interest statement

M.L. received financial grants (honoraria and speaking) from Ackea, Alnylam, and Pfizer, and travel grants from Ackea, Alnylam, Pfizer, Kedrion, Csl Behring, and Grifols; G.B. received financial grants (honoraria and speaking) from Alnylam and travel grants from Pfizer, Alnylam, and Grifols; A.D.P. received travel grants from Pfizer; G.M.F. acknowledges donations from Akcea and Pfizer to support activities of his research unit, financial support from Pfizer, Kedrion, and Akcea for participation in national and international meetings, and participation in the advisory boards of Vitacess, Alnylam, and Akcea; speaker honorarium from Akcea; S.F. received financial grants (honoraria and speaking) from Alnylam, Akcea, and Pfizer and travel grants from Alnylam and Akcea; A.M. discloses having been on the advisory board for Alnylam Therap., Akcea Therap., and Pfizer, and she is also the principal investigator in clinical trials sponsored by Alnylam Therap.; D.P. received financial grants (honoraria and speaking) from Alnylam, Akcea, Pfizer, and Inflectis, and travel grants from Kedrion and Pfizer; A.R. received travel grants from Pfizer and Csl Behring, and a financial grant from Akcea; M.S. received financial grants (honoraria and speaking) from Ackea and Alnylam and travel grants from Grifols. Other authors have no potential conflicts of interest to be disclosed. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Sural nerve biopsies from hATTR patients. Semithin sections are stained with toluidine blue. (a) A biopsy from a 63-year-old Val30Met patient showing a marked loss of myelinated fibers. (b) A biopsy from a 74-year-old Phe64Leu patient with complete loss of myelinated fibers.
Figure 2
Figure 2
Sural nerve biopsies from a 71-year-old Tyr78Phe (a) and from a 68-year-old Phe64Leu (b) hATTR patients. Semithin sections stained with toluidine blue. An inhomogeneous interfascicular fiber loss is evident (a): in two fascicles only isolated myelin fibers were present while other fascicles show an asymmetrical fiber loss. An inhomogeneous intrafascicular fiber loss is present (b).
Figure 3
Figure 3
Sural nerve biopsy from a 69-year-old Tyr78Phe patient (a): semithin section stained with toluidine blue. A moderate fiber loss is observed. Many fibers are surrounded by thin myelin sheath. Several regenerating clusters are present. Teased fibers examination from a 44-year-old patient with Glu89Gln (b) and from a 73-year-old patient with Phe64Leu (c). A segmental demyelination is present in b while a paranodal demyelination is noted in c.
Figure 4
Figure 4
Sural nerve biopsies from a 61-year-old Val32Ala (a) and from a 74-year-old Val30Met (b) hATTR patients. Macrophages are depicted by CD68 (a). Some T lymphocytes are labelled by CD3 (b).
Figure 5
Figure 5
Sural nerve biopsies from a 76-year-old Val30Met (a) and from a 74-year-old Phe64Leu (b) hATTR patients. Congo red staining. Abundant amyloid congophilic deposits are evident in a, while no deposits are present in (b).
Figure 6
Figure 6
Sural nerve biopsy from a 73-year-old Val30Met hATTR patient. H&E staining (a) showed abundant TTR amyloid deposition confirmed also by Congo red staining (b) and by immunofluorescence with anti-TTR antibodies (c).
Figure 7
Figure 7
Sural nerve biopsy from a 76-year-old Val30Met hATTR patient. Semithin section stained with Toluidine blue (a) showed amyloid deposition confirmed also by H&E (b) and Congo red (c) staining. However, immunofluorescence with anti-TTR (d), anti-kappa light chain (e), and anti-lambda light chain (f) resulted not specific for TTR amyloidosis. No MGUS was detected in this patient.
Figure 8
Figure 8
Electron microscope examination of sural nerve biopsies from hATTR patients. Ultrathin sections stained with uranyl acetate and lead citrate. Amyloid deposits are evident in a biopsy from a 65-year-old Val30Met patient (a,b). Amyloid from a 73-year-old Val30Met patient shows typical fibrillar structure (c). Unmyelinated fibers from a 74-year-old Phe64Leu patient are reduced and replaced by collagen pockets (d).
See this image and copyright information in PMC

References

    1. Plante-Bordeneuve V., Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011;10:1086–1097. doi: 10.1016/S1474-4422(11)70246-0. - DOI - PubMed
    1. Ruberg F.L., Berk J.L. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126:1286–1300. doi: 10.1161/CIRCULATIONAHA.111.078915. - DOI - PMC - PubMed
    1. Benson M.D., Kincaid J.C. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007;36:411–423. doi: 10.1002/mus.20821. - DOI - PubMed
    1. Luigetti M., Conte A., Del Grande A., Bisogni G., Madia F., Lo Monaco M., Laurenti L., Obici L., Merlini G., Sabatelli M. TTR-related amyloid neuropathy: Clinical, electrophysiological and pathological findings in 15 unrelated patients. Neurol. Sci. 2013;34:1057–1063. doi: 10.1007/s10072-012-1105-y. - DOI - PubMed
    1. Russo M., Mazzeo A., Stancanelli C., Di Leo R., Gentile L., Di Bella G., Minutoli F., Baldari S., Vita G. Transthyretin-related familial amyloidotic polyneuropathy: Description of a cohort of patients with Leu64 mutation and late onset. J. Peripher. Nerv. Syst. 2012;17:385–390. doi: 10.1111/j.1529-8027.2012.00436.x. - DOI - PubMed